Our findings that expression of NUP98-HOXD13 (NHD13), NUP98-TOP1, NUP98-RAL1GDS, Lin28b, or Hoxa9 lead to a variety of hematopoietic neoplasms have been previously reported. In order to better understand the leukemogenicity of NUP98 fused to non-HOX genes, we generated mice that expressed a NUP98-PHF23 (NP23) fusion in hematopoietic cells. Almost 100% of these mice develop leukemia within 1 year of life; the leukemic phenotype is very broad, including T and B cell leukemias, myeloid leukemias, and erythroid leukemias. A subset of NP23 mice developed a leukemia of B1 progenitor origin. These leukemias had a B1 progenitor immunophenotype and preferential usage of V regions utilized by B1 lymphocytes. Similar to normal B1 progenitors, these pro B1 leukemias express CRLF2, a subunit for the TSLP receptor. Interestingly, CRLF2 is overexpressed due to chromosomal rearrangement in over 10% of B cell precursor ALL patients; a preliminary survey suggest that patients with CRLF2 overexpression preferentially utilize V regions used in B1 lymphocytes, suggesting that these B cell precursor ALL may be derived from B1 progenitors. Finally, whole exome sequence (WES) analysis of these leukemias revealed that all have mutations involving Bcor and Jake/Stat pathway genes, suggesting a genetic mechanism for this disease. The NP23 fusion leads to stem cell self renewal, the Bcor mutation blocks B cell differentiation, and the Jak/Stat mutation leads to hyperproliferation. A manuscript describing these findings has been submitted. NP23 leukemias consistently overexpress a novel gene designated Bahcc1 (for Bromo Adjacent Homology Domain And Coiled-Coil Containing 1). Publicly available expression data indicates that BAHCC1 is overexpressed in several distinct subsets of AML. We are in the process of generating transgenic mice that overexpress the Bahcc1 gene in hematopoietic cells. A large series of pediatric AML patients has demonstrated that over 5% of patients have a NUUP98-NSD1 fusion, and that this fusion predicts a poor response to chemotherapy. We have cloned a NUP98-NSD1 fusion into the Vav1 expression vector, and generated mice that have incorporated the transgene. We are currently generating a cohort of these mice to determine if they are predisposed to AML. We have generated mice that express a U2AF1 S34F mutation. although these mice do not seem to be prone to myelodysplastic syndrome or AML, lineage negative BM cells from the U2AF1 mutant mice are consistently outcompeted by WT bone marrow in a competitive transplant model. Moreover, a low percentage of U2AF1 mice have developed clonal B cell malignancies at an advanced age; this finding is of interest given that 10-15% of variant hairy cell leukemia patients have acquired a U2AF1 S34F mutation.